The Depressor and Vasodilator Effects of Rutaecarpine are Mediated by Calcitonin Gene-Related Peptide

Abstract

Previous studies have shown that rutaecarpine has depressor and vasodilator effects, and activates vanilloid receptors to evoke calcitonin gene-related peptide (CGRP) release. In the present study, we examined whether the depressor and vasodilator effects of rutaecarpine are related to the stimulation of endogenous CGRP release via activation of vanilloid receptors in rats. Rutaecarpine (30, 100, or 300 μg/kg, i. v.) caused a depressor effect concomitantly with an increase in the plasma concentrations of CGRP in a dose-dependent manner, and the effects of rutaecarpine were abolished by pretreatment with capsaicin (50 mg/kg, s. c.) which depletes neurotransmitters in sensory nerves. In aortic and superior mesenteric arterial rings, rutaecarpine (10 ^{- 7} - 10 ^{- 5} M) or capsaicin (3 × 10 ^{- 9} - 3 × 10 ^{- 6} M) caused a concentration-dependent vasodilator response, which was significantly attenuated by capsazepine (10 ^{- 5} M), a competitive vanilloid receptor antagonist, or by CGRP-(8 - 37) (10 ^{- 6} M), a selective CGRP receptor antagonist. After pretreatment with capsaicin (10 ^{- 5} M) for 20 min, vasodilator responses to rutaecarpine were also markedly attenuated. Similarly, pretreatment with rutaecarpine (10 ^{- 5} M) for 20 min also attenuated vasodilator responses to capsaicin. These results suggest that the depressor and vasodilator effects of rutaecarpine are related to stimulation of endogenous CGRP release via activation of vanilloid receptors in rats.

Evodia rutaecarpa - Rutaceae - rutaecarpine - calcitonin gene-related peptide - vanilloid receptor - capsaicin - rat

References

• 1 Tang W, Eisenbrand D. Evodia rutaecarpa (Juss) Benth. In: Tang W, Eisenbrand D, editors Chinese drugs of plant origin. Springer Verlag Berlin; 1992: pp. 509-14
• 2 Chiou W F, Shum A Y, Liao J F, Chen C F. Studies of the cellular mechanisms underlying the vasorelaxant effects of rutaecarpine, a bioactive component extracted from an herbal drug.  J Cardiovasc Pharmacol. 1997;  29 490-8
• 3 Wang G J, Wu X C, Chen C F, Lin L C, Huang Y T, Shan J, Pang P K. Vasorelaxing action of rutaecarpine: effects of rutaecarpine on calcium channel activities in vascular endothelial and smooth muscle cells.  J Pharmacol Exp Ther. 1999;  289 1237-44
• 4 Kobayashi Y, Hoshikuma K, Nakano Y, Yokoo Y, Kamiya T. The positive inotropic and chronotropic effects of evodiamine and rutaecarpine, indoloquinazoline alkaloids isolated from the fruits of Evodia rutaecarpa, on the guinea-pig isolated right atria: possible involvement of vanilloid receptors.  Planta Med. 2001;  67 244-8
• 5 Hu C P, Xiao L, Deng H W, Li Y J. The cardioprotection of rutaecarpine is mediated by endogenous calcitonin related-gene peptide through activation of vanilloid receptors in guinea-pig hearts.  Planta Med. 2002;  68 705-9
• 6 Franco-Cereceda A. Calcitonin gene-related peptide and tachykinins in relation to local sensory control of cardiac contractility and coronary vascular tone.  Acta Physiol Scand. 1988;  133 ( 596) 1-63
• 7 Zygmunt P M, Petersson J, Andersson D A, Chuang H H, Sørgård M, Di Marzo V, Julius D, Högestätt E D. Vanilloid receptors on sensory nerves mediate the vasodilator action of anadamide.  Nature. 1999;  400 452-7
• 8 Kawasaki H, Takasaki K, Saito A, Goto K. Calcitonin gene-related peptide acts as a novel vasodilator neurotransmitter in mesenteric resistance vessel of the rat.  Nature. 1988;  335 164-7
• 9 Franco-Cereceda A, Rudehill A, Lundberg J M. Calcitonin gene-related peptide but not substance P mimics capsaicin-induced coronary vasodilation in the pig.  Eur J Pharmacol. 1987;  142 235-43
• 10 Hoover D B, Hossler F E. Vasoconstrictor and dilator responses to neurokinin A in isolated guinea pig heart.  Peptides. 1993;  14 29-36
• 11 Gao Y J, Nishimura Y, Suzuki A, Higashino H. Reactivity of intrarenal arteries to vasoconstrictor and vasorelaxant polypeptides in adult stroke-prone spontaneously hypertensive rats.  J Smooth Muscle Res. 1999;  35 125-34
• 12 Li Y J, Duckles S P. Effect of endothelium on the actions of sympathetic and sensory nerves in the perfused rat mesentery.  Eur J Pharmacol. 1992;  210 23-30
• 13 Nishimura Y, Suzuki A. Relaxant effects of vasodilator peptides on isolated basilar arteries from stroke-prone spontaneously hypertensive rats.  Clin Exp Pharmacol Physiol. 1997;  24 157-61
• 14 Lee T J, Saito A, Berezin I. Vasoactive intestinal polypeptide-like substance: the potential transmitter for cerebral vasodilation.  Science. 1984;  224 898-901
• 15 Shirahase H, Murase K, Kanda M, Kurahashi K, Nakamura S. Endothelium-dependent contraction induced by substance P in canine cerebral arteries: involvement of NK1 receptors and thromboxane A2.  Life Sci. 1999;  64 211-9
• 16 Yoshimoto R, Mitsui-Saito M, Ozaki H, Karaki H. Effects of adrenomedullin and calcitonin gene-related peptide on contractions of the rat aorta and porcine coronary artery.  Br J Pharmacol. 1998;  123 1645-54
• 17 Garry M G, Walton L P, Davis M A. Capsaicin-evoked release of immunoreactive calcitonin gene-related peptide from the spinal cord is mediated by nitric oxide but not by cyclic GMP.  Brain Res. 2000;  861 208-19
• 18 Li Y J, Peng J. The cardioprotection of CGRP-mediated preconditionig.  Eur J Pharmacol. 2002;  442 173-7
• 19 Moon T C, Murakami M, Kudo I, Son K H, Kim H P, Kang S S, Chang H W. A new class of COX-2 inhibitor, rutaecarpine from Evodia rutaecarpa .  Inflamm Res. 1999;  48 621-5
• 20 Wu S N, Lo Y K, Chen H, Li H F, Chiang H T. Rutaecarpine-induced block of delayed rectifier K⁺ current in NG108 - 15 neuronal cells.  Neuropharmacology. 2001;  41 834-43